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PDF, Also Known As Version of Record King’s Research Portal DOI: 10.1186/s13023-015-0238-5 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Thoenes, M., Zimmermann, U., Ebermann, I., Ptok, M., Lewis, M. A., Thiele, H., Morlot, S., Hess, M. M., Gal, A., Eisenberger, T., Bergmann, C., Nürnberg, G., Nürnberg, P., Steel, K. P., Knipper, M., & Bolz, H. J. (2015). OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67). Orphanet Journal of Rare Diseases, 10(1), [15]. https://doi.org/10.1186/s13023-015-0238-5 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. 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Orphanet Journal of Rare Diseases (2015) 10:15 DOI 10.1186/s13023-015-0238-5 RESEARCH Open Access OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67) Michaela Thoenes1, Ulrike Zimmermann2, Inga Ebermann1, Martin Ptok3, Morag A Lewis4, Holger Thiele5, Susanne Morlot6, Markus M Hess7, Andreas Gal8, Tobias Eisenberger9, Carsten Bergmann9,10, Gudrun Nürnberg5, Peter Nürnberg5,11, Karen P Steel4, Marlies Knipper2 and Hanno Jörn Bolz1,9* Abstract Background: Early-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family. Methods: A panel of 66 known deafness genes was analyzed for mutations by next-generation sequencing (NGS) in the index patient. We then conducted genome-wide linkage analysis, and whole-exome sequencing was carried out with samples of two patients. Expression of Osbpl2 in the mouse cochlea was determined by immunohistochemistry. Because Osbpl2 has been proposed as a target of miR-96, we investigated homozygous Mir96 mutant mice for its upregulation. Results: Onset of hearing loss in the investigated ADNSHL family is in childhood, initially affecting the high frequencies and progressing to profound deafness in adulthood. However, there is considerable intrafamilial variability. We mapped a novel ADNSHL locus, DFNA67, to chromosome 20q13.2-q13.33, and subsequently identified a co-segregating heterozygous frameshift mutation, c.141_142delTG (p.Arg50Alafs*103), in OSBPL2, encoding a protein known to interact with the DFNA1 protein, DIAPH1. In mice, Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells. We found no significant Osbpl2 upregulation at the mRNA level in homozygous Mir96 mutant mice. Conclusion: The function of OSBPL2 in the hearing process remains to be determined. Our study and the recent description of another frameshift mutation in a Chinese ADNSHL family identify OSBPL2 as a novel gene for progressive deafness. Keywords: OSBPL2, DFNA67, Autosomal dominant hearing loss Background NSHL). Approximately 20% of patients have autosomal Hearing impairment is the most common sensory dis- dominantly-inherited forms (ADNSHL) and typically order, affecting approximately 1/500 newborns. In devel- display postlingual progressive hearing impairment. oped countries, most cases are of genetic origin, and Sixty-five ADNSHL loci have been officially designated, there is extensive allelic and non-allelic heterogeneity. and 30 causative genes have been reported [1-3]. Because In 70% of hearing-impaired neonates, the sensory def- of the extensive genetic heterogeneity of hearing impair- icit is non-syndromic (non-syndromic hearing loss, ment, the identification of the causative mutation in single patients has been the exception until recently. With the advent of next-generation sequencing (NGS), deafness * Correspondence: [email protected] 1Institute of Human Genetics, University Hospital of Cologne, Cologne, genes have become accessible to comprehensive genetic Germany analysis and routine genetic testing by targeted NGS of 9 Center for Human Genetics, Bioscientia, Ingelheim, Germany “gene panels” [4]. Full list of author information is available at the end of the article © 2015 Thoenes et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Thoenes et al. Orphanet Journal of Rare Diseases (2015) 10:15 Page 2 of 10 Methods SAMtools [8], Picard (http://broadinstitute.github.io/picard/) Patients and GATK [9]. Variants were filtered against dbNSFP v2.0 Samples of the German family reported herein (Figure 1) [10], dbSNP v137, the Human Gene Mutation Database were obtained with written informed consent. Clinical (HGMD® Professional 2013.2) [11] and our in-house data- investigations were conducted according to the Declar- base. The cutoff for the maximum minor allele frequency ation of Helsinki, and the study was approved by the (MAF) was set to 1% [12]. Nonsense, frameshift and institutional review board of the Ethics Committee of canonical splice site variants were regarded likely patho- the University Hospital of Cologne. The affected subjects genic. SNVs were assessed using SIFT [13], Mutation underwent detailed audiological evaluations (e.g., pure Taster [14], PolyPhen-2 [15], AlignGVGD [16,17], Pmut tone audiometric air conduction, bone conduction, speech [18], NNSPLICE v0.9 [19] and NetGene2 [20,21]. SeqPilot reception threshold, otoacoustic emissions, and imped- SeqNext module (v4.0.1, JSI medical systems) was used ance audiometry, phoneme discrimination), except IV:12 for visualization and final assessment of SNVs. who reports intermittent hearing impairment (related to stress). Following the recommendations of the EU HEAR project [5], hearing loss was classified as mild Linkage analysis and locus designation (20 – 40 dB), moderate (41 – 70 dB), severe (71 – 95 dB), DNA samples from seven affected and six unaffected or profound (>95 dB). This classification, however, was members of the family (Figure 1) were genotyped using difficult in some cases, because at least two patients the Affymetrix GeneChip Human Mapping 10 K SNP (V:2, V:3) had near normal hearing in the 250 – 1000 Hz array Xba142. The gender was verified by counting het- region, but a loss of about 70 – 90 dB in the higher erozygous single nucleotide polymorphisms (SNPs) on frequencies. the X chromosome. Relationship errors were evaluated with the help of the program Graphical Representation of GJB2 analysis and targeted NGS of a deafness gene panel Relationships [22]. Linkage analysis was performed assum- The GJB2 gene was directly sequenced in the index ing autosomal dominant inheritance, full penetrance, patient, IV:10. His sample was then subjected to NGS and a disease gene frequency of 0.0001. Multipoint LOD for 66 genes (1,259 coding exons) that have been associ- scores were calculated using the program ALLEGRO [23]. ated with NSHL and selected forms of SHL on a MiSeq Haplotypes were reconstructed with ALLEGRO and system (Illumina) as described previously [6]. In brief, presented graphically with HaploPainter [24]. All data sheared DNA was ligated to bar-coded adaptors for handling was performed using the graphical user interface multiplexing. Exons were targeted by an in-solution ALOHOMORA [25]. customized sequence capture library (NimbleGen). Amp- Following the identification of the causative mutation in lified enriched DNA was directly subjected to NGS OSBPL2, DFNA67 was assigned as a novel locus designa- (MiSeq). Reads were mapped against the hg19 human tion for ADNSHL by the Human Gene Nomenclature reference genome using BWA [7] and processed with Committee, HGNC. Figure 1 Pedigree and genotypes of the DFNA67 family. M, OSBPL2 mutation; WT, wildtype. Blue stars, individuals whose samples were subjected to genome-wide SNP genotyping for linkage
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